title: Upregulation of tissue factor by activated Stat3 contributes to malignant pleural effusion generation via enhancing tumor metastasis and vascular permeability in lung adenocarcinoma.
abstract: Malignant pleural effusion (MPE) is a poor prognostic sign for patients with lung cancer. Tissue factor (TF) is a coagulation factor that participates in angiogenesis and vascular permeability and is abundant in MPE. We previously demonstrated that autocrine IL-6-activated Stat3 contributes to tumor metastasis and upregulation of VEGF, resulting in the generation of MPE in lung adenocarcinoma. In this study, we found IL-6-triggered Stat3 activation also induces TF expression. By using pharmacologic inhibitors, it was shown that JAK2 kinase, but not Src kinase, contributed to autocrine IL-6-induced TF expression. Inhibition of Stat3 activation by dominant negative Stat3 (S3D) in lung adenocarcinoma suppressed TF-induced coagulation, anchorage-independent growth in vitro, and tumor growth in vivo. Consistently, knockdown of TF expression by siRNA resulted in a reduction of anchorage-independent growth of lung adenocarcinoma cells. Inhibition of TF expression also decreased the adhesion ability of cancer cells in normal lung tissues. In the nude mouse model, both lung metastasis and MPE generation were decreased when PC14PE6/AS2-siTF cells (TF expression was silenced) were intravenously injected. PC14PE6/AS2-siTF cells also produced less malignant ascites through inhibition of vascular permeability. In summary, we showed that TF expression plays a pivotal role in the pathogenesis of MPE generation via regulating of tumor metastasis and vascular permeability in lung adenocarcinoma bearing activated Stat3.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan ; Cancer Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsuan-Heng
authors.initials: HH
authors.lastname: Yeh
authors.forename: Wen-Tsan
authors.initials: WT
authors.lastname: Chang
authors.forename: Kuang-Chu
authors.initials: KC
authors.lastname: Lu
authors.forename: Wu-Wei
authors.initials: WW
authors.lastname: Lai
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
mesh_terms: D000230:Adenocarcinoma / Q000150:complications*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008156:Luciferases; D008175:Lung Neoplasms / Q000150:complications*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D016066:Pleural Effusion, Malignant / Q000209:etiology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013925:Thromboplastin; D008156:Luciferases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2